Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity. Next we show that giving up smoking, educational attainment, openness to new experience and high-density lipoprotein (HDL) cholesterol levels are most positively genetically correlated with lifespan while susceptibility to coronary artery disease (CAD), cigarettes smoked per day, lung cancer, insulin resistance and body fat are most negatively correlated. We suggest that the effect of education on lifespan is principally mediated through smoking while the effect of obesity appears to act via CAD. Using instrumental variables, we suggest that an increase of one body mass index unit reduces lifespan by 7 months while 1 year of education adds 11 months to expected lifespan.
Bibliographical noteFunding Information:
We thank the UK Biobank Resource, approved under application 8304; we acknowledge funding from the UK Medical Research Council Human Genetics Unit. We would like to thank the authors of LDHub and MRbase and all the groups who contributed summary statistics there, as well as the BCAC and CHARGE-CRP consortia for sharing their summary statistics with us directly. We also thank Neil Robertson, Wellcome Trust Centre for Human Genetics, Oxford, for use of his author details management software, Authorial, and Tom Haller of the University of Tartu, for tailoring RegScan so we could use it with compressed files. We would also like to thank the researchers, funders and participants of all the contributing cohorts. Study specific acknowledgements are listed in Supplementary Note 1.
28Department of Medicine, GeneSTAR Research Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. 29Centre for Epidemiology, Division of Population Health, Health Services Research & Primary Care, The University of Manchester, Manchester, Greater, Manchester M13 9PL, UK. 30Center for Biomedicine, European Academy of Bozen/Bolzano (EURAC), (Affiliated Institute of the University of Lübeck, Lübeck, Germany), Bolzano 39100, Italy. 31Institute of Genetic and Biomedical Research - Support Unity, National Research Council of Italy, Sassari 07100, Italy. 32Institute of Molecular Genetics, National Research Council of Italy, Pavia 27100, Italy. 33Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore City, MD 21224, USA. 34Department of Clinical Chemistry, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Tampere 33014, Finland. 35Health Science Center at Houston, UTHealth School of Public Health, University of Texas, Houston, TX 77030, USA. 36Department of Biomedicine–Human Genetics, Aarhus University, DK-8000 Aarhus C, Denmark. 37Centre for Integrative Sequencing, iSEQ, Aarhus University, DK-8000 Aarhus C, Denmark. 38Centre for Genomic & Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. 39Division of Epidemiology & Community Health, School of Public Health, University of Minnesota, Minneapolis, MN 55454, USA. 40Charité Research Group on Geriatrics, Charité, Universitätsmedizin Berlin, Berlin 13347, Germany. 41Lipid Clinic at the Interdisciplinary Metabolism Center, Charité, Universitätsmedizin Berlin, Berlin 13353, Germany. 42Institute for Medical and Human Genetics, Charité, Universitätsmedizin Berlin, Berlin 13353, Germany. 43Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, MI 48014, USA. 44Robertson Center for biostatistics, University of Glasgow, Glasgow G12 8QQ, UK. 45IRCCS Neuromed, Pozzilli (IS) 86077, Italy. 46Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27514, USA. 47Institute of Cardiovascular Science, University College London, London WC1E 6BT, UK. 48Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen 2300, Denmark. 49Department of Microbiology and Immunology, Fimlab Laboratories and Faculty of Medicine and Life Sciences, University of Tampere, Tampere 33014, Finland. 50Gerontology Research Center, Tampere, Finland, Faculty of Social Sciences, University of Tampere, Tampere 33104, Finland. 51Genetic and Molecular Epidemiology Group, Institute of Neurogenetics, University of Lübeck, 23562 Lübeck, Germany. 52Center for Lifespan Psychology, Max Planck Institute for Human Development, Berlin 14195, Germany. 53Max Planck UCL Centre for Computational Psychiatry and Ageing Research, Berlin 14195, Germany. 54Department of Statistics, University of Auckland, Auckland 1010, New Zealand. 55Department of Medicine, Internal Medicine, Lausanne University Hospital, Lausanne 1011, Switzerland. 56Division of Population Health, Health Services Research & Primary Care, School of Health Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, Greater Manchester M13 9PL, UK. 57TH Chan School of Public Health, Harvard Medical School, Boston, MA 02115, USA. 58Austrian Stroke Prevention Study, Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz 8010, Austria. 59Section of Molecular Epidemiology, Department of medical statistics, Leiden University Medical Center, Leiden 2300RC, The Netherlands. 60Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, UK. 61Cardiovascular Health Research Unit, Division of Cardiology, University of Washington, Seattle, WA 98101, USA. 62NORMENT, KG Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo, Oslo 0450, Norway. 63Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics & Cardiogenetics, University of Lübeck, Lübeck 23562, Germany. 64Neuroepidemiology and Ageing Research Group, School of Public Health, Imperial College, London W6 8RP, UK. 65Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Manchester Academic Health Science Centre, University of Manchester, Manchester, Greater Manchester M13 9PL, UK. 66Cardiovascular Health Research Unit, Departments of Epidemiology, Medicine and Health Services, University of Washington, Seattle, WA 98101, USA. 67Kaiser Permanente Washington Health Research Institute, Seattle, WA 98101, USA. 68Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS 39216, USA. 69BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow G12 8TD, UK. 70Program in Medical and Population Genetics, Broad Institute, Broad Institute, Cambridge, MA 02142, USA. Peter K. Joshi and Nicola Pirastu contributed equally to this work
© 2017 The Author(s).